调节性T细胞作为抗癌治疗的潜在靶点
Regulatory T Cells as Potential Therapeutic Targets for Anticancer Therapy
摘要: 免疫逃避是大多数人类恶性肿瘤的特征,并通过各种机制诱导。免疫抑制细胞,包括调节性T细胞(Regulatory T cells, Tregs)和髓源性抑制细胞(myeloid-derived suppressor cell, MDSCs),是帮助肿瘤逃避免疫监视的关键介质。此篇综述讨论了Treg在癌症进展中的作用、当前靶向Treg的治疗策略以及临床应用前景。
Abstract: Immune evasion characterizes most human malignancies and is induced by various mechanisms. Immunosuppressor cells, including Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), are key mediators that help tumors evade immune surveillance. This review discusses the role of Tregs in cancer progression, current Treg-targeting therapeutic strategies, and clinical pro-spects.
文章引用:殷方田, 姜军. 调节性T细胞作为抗癌治疗的潜在靶点[J]. 临床医学进展, 2022, 12(10): 9267-9272. https://doi.org/10.12677/ACM.2022.12101340

参考文献

[1] Li, C., Jiang, P., Wei, S., et al. (2020) Regulatory T Cells in Tumor Microenvironment: New Mechanisms, Potential Therapeutic Strategies and Future Prospects. Molecular Cancer, 19, Article No. 116. [Google Scholar] [CrossRef] [PubMed]
[2] Hariyanto, A.D., Permata, T.B.M. and Gondhowiardjo, S.A. (2021) Role of CD4+ CD25+ FOXP3+ TReg Cells on Tumor Immunity. Immunological Medicine, 45, 94-107.
[3] Saito, T., Nishikawa, H., Wada, H., et al. (2016) Two FOXP3(+)CD4(+) T Cell Subpopulations Distinctly Control the Prog-nosis of Colorectal Cancers. Nature Medicine, 22, 679-684. [Google Scholar] [CrossRef] [PubMed]
[4] Wing, J.B., Tanaka, A. and Sakaguchi, S. (2019) Human FOXP3(+) Regulatory T Cell Heterogeneity and Function in Autoimmunity and Cancer. Immunity, 50, 302-316. [Google Scholar] [CrossRef] [PubMed]
[5] Ohue, Y. and Nishikawa, H. (2019) Regulatory T(Treg) Cells in Cancer: Can Treg Cells Be a New Therapeutic Target? Cancer Science, 110, 2080-2089. [Google Scholar] [CrossRef] [PubMed]
[6] Kim, J.H., Kim, B.S. and Lee, S.K. (2020) Regulatory T Cells in Tumor Microenvironment and Approach for Anticancer Immunotherapy. Immune Network, 20, e4. [Google Scholar] [CrossRef] [PubMed]
[7] Ha, D., Tanaka, A., Kibayashi, T., et al. (2019) Differential Control of Human Treg and Effector T Cells in Tumor Immunity by Fc-Engineered Anti-CTLA-4 Antibody. Proceedings of the Na-tional Academy of Sciences of the United States of America, 116, 609-618. [Google Scholar] [CrossRef] [PubMed]
[8] Togashi, Y., Shitara, K. and Nishikawa, H. (2019) Regulatory T Cells in Cancer Immunosuppression-Implications for Anticancer Therapy. Nature Reviews Clinical Oncology, 16, 356-371. [Google Scholar] [CrossRef] [PubMed]
[9] Platten, M., Nollen, E.A.A., Röhrig, U.F., et al. (2019) Tryptophan Metabolism as a Common Therapeutic Target in Cancer, Neurodegeneration and Beyond. Nature Reviews Drug Discovery, 18, 379-401. [Google Scholar] [CrossRef] [PubMed]
[10] Angelin, A., Gil-De-Gómez, L., Dahiya, S., et al. (2017) Foxp3 Reprograms T Cell Metabolism to Function in Low- Glucose, High-Lactate Environments. Cell Metabolism, 25, 1282-1293.e1287. [Google Scholar] [CrossRef] [PubMed]
[11] Sek, K., Mølck, C., Stewart, G.D., et al. (2018) Targeting Adeno-sine Receptor Signaling in Cancer Immunotherapy. International Journal of Molecular Sciences, 19, Article No. 3837. [Google Scholar] [CrossRef] [PubMed]
[12] Tanaka, A. and Sakaguchi, S. (2019) Targeting Treg Cells in Cancer Immunotherapy. European Journal of Immunology, 49, 1140-1146. [Google Scholar] [CrossRef] [PubMed]
[13] Kochin, V. and Nishikawa, H. (2019) Meddling with Meddlers: Curbing Regulatory T Cells and Augmenting Antitumor Immunity. Nagoya Journal of Medical Science, 81, 1-18.
[14] Xu, J., Li, X., Yuan, Q., et al. (2021) The Semaphorin 4A-Neuropilin 1 Axis Alleviates Kidney Ischemia Reperfusion Injury by Promoting the Stability and Function of Regulatory T Cells. Kidney International, 100, 1268-1281. [Google Scholar] [CrossRef] [PubMed]
[15] Liu, X.Q., Yao, Y., Mu, J.W., et al. (2021) Semaphorin 4A Re-stricts Tumor Progression by Inhibiting Angiogenesis of Oral Squamous Cell Carcinoma Cells. Tissue Cell, 69, Article ID: 101485. [Google Scholar] [CrossRef] [PubMed]
[16] Chapoval, S.P., Hritzo, M., Qi, X., et al. (2019) Sem-aphorin 4A Stabilizes Human Regulatory T Cell Phenotype via Plexin B1. ImmunoHorizons, 3, 71-87. [Google Scholar] [CrossRef] [PubMed]
[17] Chen, W.M., Liu, J.L., Chuang, H.C., et al. (2020) Helios Expression in Tumor-Infiltrating Lymphocytes Correlates with Overall Survival of Advanced Gastric Cancer Patients. Life (Basel), 10, E189. [Google Scholar] [CrossRef] [PubMed]
[18] Lam, A.J., Uday, P., Gillies, J.K., et al. (2022) Helios Is a Marker, Not a Driver, of Human Treg Stability. European Journal of Immunology, 52, 75-84. [Google Scholar] [CrossRef] [PubMed]
[19] Nakagawa, H., Sido, J.M., Reyes, E.E., et al. (2016) Instability of He-lios-Deficient Tregs Is Associated with Conversion to a T-Effector Phenotype and Enhanced Antitumor Immunity. Pro-ceedings of the National Academy of Sciences of the United States of America, 113, 6248-6253. [Google Scholar] [CrossRef] [PubMed]
[20] Ahmadzadeh, M., Pasetto, A., Jia, L., et al. (2019) Tu-mor-Infiltrating Human CD4(+) Regulatory T Cells Display a Distinct TCR Repertoire and Exhibit Tumor and Neoanti-gen Reactivity. Science Immunology, 4, eaao4310. [Google Scholar] [CrossRef] [PubMed]
[21] Solomon, I., Amann, M., Goubier, A., et al. (2020) CD25-T(reg)-Depleting Antibodies Preserving IL-2 Signaling on Effector T Cells Enhance Effector Activation and Anti-tumor Immunity. Nature Cancer, 1, 1153-1166. [Google Scholar] [CrossRef] [PubMed]
[22] Vazquez-Lombardi, R., Loetsch, C., Zinkl, D., et al. (2017) Po-tent Antitumour Activity of Interleukin-2-Fc Fusion Proteins Requires Fc-Mediated Depletion of Regulatory T-Cells. Nature Communications, 8, Article No. 15373. [Google Scholar] [CrossRef] [PubMed]
[23] Sharma, A., Subudhi, S.K., Blando, J., et al. (2019) Anti-CTLA-4 Immunotherapy does Not Deplete FOXP3(+) Regulatory T Cells (Tregs) in Human Cancers. Clinical Cancer Research, 25, 1233-1238. [Google Scholar] [CrossRef
[24] Lewis, D.J. and Rook, A.H. (2020) Mogamulizumab in the Treatment of Advanced Mycosis Fungoides and Sézary Syndrome: Safety and Efficacy. Expert Review of Anticancer Therapy, 20, 447-452. [Google Scholar] [CrossRef] [PubMed]
[25] Moser, B. (2022) Chemokine Receptor-Targeted Therapies: Special Case for CCR8. Cancers, 14, Article No. 511. [Google Scholar] [CrossRef] [PubMed]
[26] Campbell, J.R., Mcdonald, B.R., Mesko, P.B., et al. (2021) Fc-Optimized Anti-CCR8 Antibody Depletes Regulatory T Cells in Human Tumor Models. Cancer Research, 81, 2983-2994. [Google Scholar] [CrossRef
[27] Whiteside, S.K., Grant, F.M., Gyori, D.S., et al. (2021) CCR8 Marks Highly Suppressive Treg Cells within Tumours but Is Dispensable for Their Accumulation and Suppressive Function. Immunology, 163, 512-520. [Google Scholar] [CrossRef] [PubMed]
[28] Diab, A., Hamid, O., Thompson, J.A., et al. (2022) A Phase I, Open-Label, Dose-Escalation Study of the OX40 Agonist Ivuxolimab in Patients with Locally Advanced or Metastatic Cancers. Clin-ical Cancer Research, 28, 71-83. [Google Scholar] [CrossRef
[29] Zappasodi, R., Sirard, C., Li, Y., et al. (2019) Rational De-sign of Anti-GITR-Based Combination Immunotherapy. Nature Medicine, 25, 759-766. [Google Scholar] [CrossRef] [PubMed]
[30] Li, D.Y. and Xiong, X.Z. (2020) ICOS(+) Tregs: A Functional Subset of Tregs in Immune Diseases. Frontiers in Immunology, 11, Article No. 2104. [Google Scholar] [CrossRef] [PubMed]
[31] Han, Y., Dong, Y., Yang, Q., et al. (2018) Acute Myeloid Leuke-mia Cells Express ICOS Ligand to Promote the Expansion of Regulatory T Cells. Frontiers in Immunology, 9, Article No. 2227. [Google Scholar] [CrossRef] [PubMed]
[32] Amatore, F., Gorvel, L. and Olive, D. (2018) Inducible Co-Stimulator (ICOS) as a Potential Therapeutic Target for Anti-Cancer Therapy. Expert Opinion on Therapeutic Tar-gets, 22, 343-351. [Google Scholar] [CrossRef] [PubMed]
[33] Khair, D.O., Bax, H.J., Mele, S., et al. (2019) Combining Immune Checkpoint Inhibitors: Established and Emerging Targets and Strategies to Improve Outcomes in Melanoma. Frontiers in Immunology, 10, Article No. 453. [Google Scholar] [CrossRef] [PubMed]
[34] Kvarnhammar, A.M., Veitonmäki, N., Hägerbrand, K., et al. (2019) The CTLA-4 x OX40 Bispecific Antibody ATOR-1015 Induces Anti-Tumor Effects through Tumor-Directed Immune Activation. Journal for ImmunoTherapy of Cancer, 7, Article No. 103. [Google Scholar] [CrossRef] [PubMed]
[35] Tauriello, D.V.F., Palomo-Ponce, S., Stork, D., et al. (2018) TGFβ Drives Immune Evasion in Genetically Reconstituted Colon Cancer Metastasis. Nature, 554, 538-543. [Google Scholar] [CrossRef] [PubMed]
[36] Mariathasan, S., Turley, S.J., Nickles, D., et al. (2018) TGFβ Attenuates Tumour Response to PD-L1 Blockade by Contributing to Exclusion of T Cells. Nature, 554, 544-548. [Google Scholar] [CrossRef] [PubMed]
[37] Holmgaard, R.B., Schaer, D.A., Li, Y., et al. (2018) Targeting the TGFβ Pathway with Galunisertib, a TGFβRI Small Molecule Inhibitor, Promotes Anti-Tumor Immunity Leading to Durable, Complete Responses, as Monotherapy and in Combination with Checkpoint Blockade. Journal for ImmunoTherapy of Cancer, 6, Article No. 47.
[38] Principe, D.R., Narbutis, M., Kumar, S., et al. (2020) Long-Term Gemcitabine Treat-ment Reshapes the Pancreatic Tumor Microenvironment and Sensitizes Murine Carcinoma to Combination Immunother-apy. Cancer Research, 80, 3101-3115. [Google Scholar] [CrossRef
[39] Principe, D.R., Park, A., Dorman, M.J., et al. (2019) TGFβ Blockade Augments PD-1 Inhibition to Promote T-Cell- Mediated Regression of Pancreatic Cancer. Molecular Cancer Therapeutics, 18, 613-620. [Google Scholar] [CrossRef
[40] Chen, X., Wang, L., Li, P., et al. (2018) Dual TGF-β and PD-1 Blockade Synergistically Enhances MAGE-A3-Specific CD8(+) T Cell Response in Esophageal Squamous Cell Carcinoma. International Journal of Cancer, 143, 2561-2574. [Google Scholar] [CrossRef] [PubMed]
[41] Boudewijns, S., Bloemendal, M., De Haas, N., et al. (2020) Autologous Monocyte-Derived DC Vaccination Combined with Cisplatin in Stage III and IV Melanoma Patients: a Prospective, Randomized Phase 2 Trial. Cancer Immunology, Immunotherapy, 69, 477-488. [Google Scholar] [CrossRef] [PubMed]
[42] Dao, T., Mun, S.S., Scott, A.C., et al. (2019) Depleting T Regu-latory Cells by Targeting Intracellular Foxp3 with a TCR Mimic Antibody. Oncoimmunology, 8, Article ID: 1570778. [Google Scholar] [CrossRef
[43] Okada, R., Maruoka, Y., Furusawa, A., et al. (2019) The Effect of Antibody Fragments on CD25 Targeted Regulatory T Cell Near-Infrared Photoimmunotherapy. Bioconjugate Chemistry, 30, 2624-2633. [Google Scholar] [CrossRef] [PubMed]
[44] Deshaies, R.J. (2020) Multispecific Drugs Herald a New Era of Biopharmaceutical Innovation. Nature, 580, 329-338. [Google Scholar] [CrossRef] [PubMed]
[45] Freeman, Z.T., Nirschl, T.R., Hovelson, D.H., et al. (2020) A Conserved Intratumoral Regulatory T Cell Signature Identifies 4-1BB as a Pan-Cancer Target. The Journal of Clinical Investigation, 130, 1405-1416. [Google Scholar] [CrossRef
[46] Cari, L., Nocentini, G., Migliorati, G., et al. (2018) Potential Effect of Tu-mor-Specific Treg-Targeted Antibodies in the Treatment of Human Cancers: A Bioinformatics Analysis. Oncoimmunol-ogy, 7, e1387705. [Google Scholar] [CrossRef